1. Field of the Invention
This invention relates to a series of novel bicyclic derivatives which exhibit in vitro and in vivo inhibition of interleukin-1.beta. converting enzyme, to compositions containing the novel bicyclic derivatives and to methods for therapeutic utility. More particularly, the interleukin 1.beta. converting enzyme inhibitors described in this invention comprise novel bicyclic derivatives of aldehydes and .alpha.-substituted methyl ketones which possess particular utility in the treatment of inflammatory and immune-based diseases of lung, central nervous system, and connective tissues.
2. Reported Developments
Interleukin 1.beta. (IL-1.beta.) protease (also known as interleukin-1.beta. converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1.beta. to the biologically active 17 kD form (Kostura, M. J.; Tocci, M. J.; Limjuco, G.; Chin, J.; Cameron, P.; Hillman, A. G.; Chartrain, N. A.; Schmidt, J. A., Proc. Nat. Acad. Sci., (1989), 86, 5227-5231 and Black, R. A.; Kronheim, S. R.; Sleath, P. R., FEBS Let., (1989), 247, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1.beta. has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, acute and chronic myelogenous leukemia and osteoporosis (Dinarello, C. A.; Wolff, S. M., New Engl. J. Med., (1993), 328, 106). A naturally occurring IL-1.beta. receptor antagonist has been used to demonstrate the intermediacy of IL-1.beta. in a number of human diseases and animal models (Hannum, C. H.; Wilcox, C. J.; Arend, W. P.; Joslin, G. G.; Dripps, D. J.; Heimdal, P. L.; Armes, L. G.; Sommer, A.; Eisenberg, S. P.; Thompson, R. C., Nature, (1990), 343, 336-340; Eisenberg, S. P.; Evans, R. J.; Arend, W. P.; Verderber, E.; Brewer, M. T.; Hannum, C. H.; Thompson, R. C., Nature (1990), 343, 341-346; Ohlsson, K.; Bjork, P.; Bergenfeldt, M.; Hageman, R.; Thompson, R. C., Nature, (1990), 348, 550-552; Wakabayashi, G., FASEB, (1991), 338-343; Pacifici, R.; et al. Proc. Natl. Acad. Sci. (1989), 86, 2398-2402 and Yamamoto, I.; et al. Cancer Rsh (1989), 49, 4242-4246). The specific role of IL-1.beta. in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C. A. et al, Cell, (1992), 69, 597-604).
The importance of these observations is well recognized by those skilled in the art and several workers have proposed and demonstrated in vivo the utility of ICE inhibitors in modifying certain IL-1.beta. mediated disease states. Some have suggested the development and therapeutic use of a small molecule inhibitor of mature IL-1.beta. formation. (See, e.g., Miller, D. K. et al. "The IL-1.beta. Converting Enzyme as a Therapeutic Target" in Immunosuppressive and Antiinflammatory Drugs; Annals of the New York Academy of Sciences; Vol. 696, pp 133-148, 1993). The following review of the current state of the art in ICE research further supports such utility of ICE inhibitors:
1) WO 9309135, published 11 May 1993, teaches that peptide-based aspartic acid arylacyloxy-and aryloxymethyl ketones are potent inhibitors of ICE in vitro. These compounds also specifically inhibited ICE in the whole cell (in vivo) by their ability to inhibit the formation of mature IL-1.beta. in whole cells. These ICE inhibitors also demonstrated utility in reducing fever and inflammation/swelling in rats.
2) Patients with Lyme disease sometimes develop Lyme arthritis. B. burgdorferi, the causative agent of Lyme disease, is a potent inducer of IL-1 synthesis by mononuclear cells. Miller et al. (Miller, L. C.; Lynch, E. A. Isa, S.; Logan, J. W.; Dinarello, C. A.; and Steere, A. C., "Balance of synovial fluid IL-1.beta. and IL-1 Receptor Antagonist and Recovery from Lyme arthritis", Lancet (1993) 341; 146-148) showed that in patients who recovered quickly from Lyme Arthritis, the balance in synovial fluid of IL-1.beta. and IL-1ra was in favor of IL-ra. When the balance was shifted in favor of IL-1.beta., it took significantly longer for the disease to resolve. The conclusion was that the excess IL-1ra blocked the effects of the IL-1.beta. in the patients studied.
3) The IL-1 receptor antagonist, Antril (Synergen), possess significant antiinflammatory activity in patients with active rheumatoid arthritis. In multicenter Phase II dose ranging study, 175 patients received subcutaneous doses of antril at 20 mg, 70 mg and 200 mg. The antagonist was found to be most effective when taken daily. After three weeks of daily treatment, patients showed a decrease in joint swelling and less disease activity. A second Phase II clinical trial is scheduled to begin in 1994 (Scrip, NO 1873, 1993).
4) IL-1 is present in affected tissues in ulcerative colitis in humans. In animal models of the disease, IL-1.beta. levels correlate with disease severity. In the model, administration of 1L-1ra reduced tissue necrosis and the number of inflammatory cells in the colon. See, Cominelli, F.; Nast, C. C.; Clark, B. D.; Schindler, R., Llerena, R.; Eysselein, V. E.; Thompson, R. C.; and Dinarello, C. A.; "Interleukin-1 Gene Expression, Synthesis, and Effect of Specific IL-1 Receptor Blockade in Rabbit Immune Complex Colitis" J. Clin. Investigations (1990) Vol. 86, pp, 972-980.
5) The IL-1 receptor antagonist, Antril (Synergen), possess significant antiinflammatory activity in patients with active rheumatoid arthritis. In a multicenter Phase II dose ranging study, 175 patients received subcutaneous doses of Antril at 20 mg, 70 mg and 200 mg seven times, three times or once per week. The antagonist was found to be most effective when taken daily. After three weeks of daily treatment, patients showed a decrease in joint swelling and less disease activity (Scrip, NO 1873, 1993).
6) IL-1ra supresses joint swelling in the PG-APS model of arthritis in rats. See Schwab, J. H.; Anderle, S. K.; Brown, R. R.; Dalldorf, F. G. and Thompson, R. C., "Pro- and Anti-Inflammatory Roles of Interelukin-1 in Recurrence of Bacterial Cell Wall-Induced Arthritis in Rats". Infect. Immun. (1991) 59; 4436-4442.
7) IL-1 ra shows efficacy in an small open-label human Rheumatoid Arthritis trial. See, Lebsack, M. E.; Paul, C. C.; Bloedow, C. C.; Burch, F. X.; Sack, M. A.; Chase, W., and Catalano, M. A. "Subcutaneous IL-1 Receptor Antagonist in Patients with Rheumatoid Arthritis", Arth. Rheum. (1991) 34; 545.
8) Soluble IL-1 receptor significantly reduces clinically the cutaneous late-phase allergic reaction. This was demostrated in a prospective, randomized, double-blind, placebo-controlled study on 15 allergic subjects. See, Mullarkey, M. F. et al. "Human Cutaneous Allergic Late-Phase Response is Inhibited by Soluble IL-1 Receptor", J. of Immunology, (1994) 152; 2033-2041.
9) IL-1 appears to be an autocrine growth factor for the proliferation of chronic myelogenous leukemia cells. Both IL-1 ra and sIL-1R inhibit colony growth in cells removed from leukemia patients. See, Estrov, Z.; Kurzrock, R.; Wetzler, M.; Kantarjian, H.; Blake, M.; Harris, D.; Gutterman, J. U.; and Talpaz, M., "Supression of Chronic Myelogenous Leukemia Colony Growth by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity". Blood (1991) 78; 1476-1484.
10) As in 6) above, but for acute myelogenous leukemia rather than chronic myelogenous leukemia. See, Estrov, Z.; Kurzrock, R.; Estey, E.; Wetzler, M.; Ferrajoli, A.; Harris, D.; Blake, M.; Guttermann, J. U.; and Talpaz, M. "Inhibition of Acute Myelogenous Leukemia Blast Proliferation by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors". (1992) Blood 79; 1938-1945.
The IL-1 receptor antagonist, Antril (Synergen), possess significant antiinflammatory activity in patients with active rheumatoid arthritis. In multicenter Phase II dose ranging study, 175 patients received subcutaneous doses of antril at 20 mg, 70 mg and 200 mg. The antagonist was found to be most effective when taken daily. After three weeks of daily treatment, patients showed a decrease in joint swelling and less disease activity. A second Phase II clinical trial is scheduled to begin in 1994 (Scrip, NO 1873, 1993).
An effective therapy has yet to be fully developed commercially for the treatment of IL-1.beta. mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.